Role of Group III Metabotropic Glutamate Receptors in Excitotoxin‐Induced Cerebellar Granule Cell Death

Abstract

Abstract:The neuronal effects of the metabotropic glutamate receptor agonist (1 S,3R)-aminocyclopentane-1 ,3-dicarboxylic acid have been studied in cultured rat cerebellar granule cells, and compared with those of the endogenous excitotoxin glutamate, and the dietary excitotoxin /3-N-methylamino-L-alanine. Glutamate,~3-N-methylamino-L-alanine, and (1 S ,3R) -aminocyclopentane-1 ,3-dicarboxylic acid all caused concentration-dependent cerebellar granule cell death over a 24-h exposure period. The metabotropic antagonist (RS) -a-methyl-4-carboxyphenylglycine reduced glutamate-, /3-N-methylamino-L-alanine-, and (1 S ,3R)-aminocyclopentane-1 ,3-dicarboxylic acid-induced death by 50, 37, and 90%, respectively. (1 S ,3R) -Aminocyclopentane-1 ,3-dicarboxylic acid-induced death was unaffected by the group I antagonist (RS)-1 -aminoindan-1 ,5-dicarboxylic acid, increased by the group II antagonist ethylglutamic acid, and markedly decreased by the group Ill antagonist (RS) -amethylserine-O-phosphate. Neither (1 S ,3R) -aminocyclopentane-1 ,3-dicarboxylic acid nor the group I agonist (RS)-3,5-dihydroxyphenylglycine caused an increase in intracellular free calcium levels. The group Ill agonist L-(+)-2-amino-4-phosphonobutyric acid also induced concentration-dependent cerebellar granule cell death, and so it was suggested that the group Ill metabotropic glutamate receptors were responsible for (1 S,3R)-aminocyclopentane-1 ,3-dicarboxylic acid-induced death. Blocking these receptors with (RS) -a-methylserine-O-phosphate also prevented a proportion of glutamate-and /3-N-methylamino-L-alanineinduced death. Key Words: (1 S,3R)-Aminocyclopentane-1 ,3-dicarboxylic acid-/3-N-Methylamino-L-alanine-Rat cerebellar granule cells-Glutamate. J. Neurochem. 71, 1280Neurochem. 71, -1288Neurochem. 71, (1998.Glutamate is the principal excitatory neurotransmitter in the mammalian brain, where it activates both ionotropic glutamate receptors and metabotropic glutamate receptors (mGluRs). Tonotropic glutamate receptors are ligand-gated ion channels that comprise NMDA and a-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) kainate subtypes (Monaghan et al., 1989). Overactivation of ionotropic receptors results in neuronal death via excitotoxicity , and some of the intracellular events that lead to death can be influenced by mGluRs (Pin and Duvoisin, 1995).mGluRs are coupled to U proteins, and this family of glutamate receptors comprises eight subtypes, to date, that are divided into three groups, based on their second messenger coupling, sequence similarity, and ligand selectivities (Pin and Duvoisin, 1995). Group I includes mGluRi and mGluR5, which are coupled to polyphosphoinositide (PPI) hydrolysis. mGluRs from groups II (mGluR2 and mGluR3) and III (mGluR4, mGluR6, mGluR7, and mGluR8) are negatively coupled to adenylate cyclase activity. In addition, an mGluR receptor coupled to phospholipase D has been identified in the hippocampus (Pellegrini-Giampetro et al., 1996). This coupling to disparate transduction pathways may underlie th...

Metabotropic Glutamate Receptor 1 Mediates the Electrophysiological and Toxic Actions of the Cycad Derivative β-N-Methylamino-l-Alanine on Substantia Nigra Pars Compacta DAergic Neurons

“…A similar drug action was also observed in a minority of DAergic neurons. BMAA has been previously reported to potently activate mGluRs in hippocampal, striatal, and cerebellar neurons (Copani et al, 1990(Copani et al, , 1991Manzoni et al, 1991;Staton and Bristow, 1998;Lobner et al, 2007). Alternatively, it predominantly activates NMDA receptors in cortical neurons (Weiss et al, 1989;Lobner et al, 2007) and AMPA/kainate receptors in spinal motoneurons (Rao et al, 2006).…”

“…It has been demonstrated that BMAA activates different types of glutamate receptors in diverse brain areas (Spencer et al, 1987;Copani et al, 1990Copani et al, , 1991Allen et al, 1993;Pai et al, 1993;Staton and Bristow, 1998;Rao et al, 2006;Lobner et al, 2007). To this regard, we aimed to explore its effect onto the "secondary" cells of the SNpc, presumably GABAergic neurons ( Fig.…”

Enzymatic Degradation Protects Neurons from Glutamate Excitotoxicity

“…The development of such antagonists as clinically useful neuroprotectants has been limited by the complex nature of glutamate receptors. Depending on the model system assessed, roles for each of several subtypes of glutamate receptors have been proposed in mediating glutamate excitotoxicity (Olney et al, 1989; Buchan et al, 1991; Kaku et al, 1991; Albers et al, 1992; Le Peillet et al, 1992; Gill, 1994; Buisson and Choi, 1995; Mukhin et al, 1996; Staton and Bristow, 1998). Lack of specificity of some glutamate receptor antagonists has also limited clinical utility, leading to unwanted side effects, such as psychosis (Carter, 1994; Muir and Lees, 1995; Turski et al, 1998).…”